Adolescence is a period of rapid change, marked by increased stress and emotion regulation difficulties, and concomitant increases in stress-related psychopathology. Although much research has been devoted to understanding the role of stress response systems, especially the HPA axis, in the development and maintenance of internalizing disorders, very little research has focused on the vulnerable adolescent period and none has been conducted prospectively beginning in infancy. Over the past 17 years, a large cohort of children participating since birth in the Wisconsin Study of Family and Work has been intensively studied to examine longitudinal associations of early stress exposure, HPA activity, and the development of childhood mental health problems. Based on these unique developmental data, the present proposal affords an unprecedented opportunity to follow this sample through adolescence, addressing novel questions regarding the role of early stress exposure in the sensitization of the HPA axis to later stress, associations with neural correlates of emotion dysregulation, and the development and course of internalizing psychopathology during this vulnerable period. To extend the existing longitudinal dataset to late adolescence, 300 adolescents and their mothers will be interviewed in grade 12 (approximate age 18). In addition, a,subset of 120 adolescents - selected on high vs. low early (age 41/) and later (ages 11,13 and 15) cortisol levels - will participate in an intensive laboratory assessment of HPA reactivity and, as part of Projects 4 and 5, neural bases of emotion regulation. Major aims are 1) to investigate the stress sensitization hypothesis in a community sample experiencing the normative stressors of adolescence; 2) to test the stress sensitization hypothesis in a formal laboratory paradigm (the Trier Social Stress Test) with high salience for adolescents; and 3) to identify the stress exposure, HPA, other stress reactivity, and neural circuitry factors, and their combinations, which best discriminate individuals with internalizing disorders by late adolescence. Relevance: This work is highly innovative, integrating the strengths of longitudinal field research with those of laboratory approaches to understand the development of the HPA stress response system and the neural circuitry implicated in adolescent vulnerability to develop stress-related psychopathology, thus providing much needed information for researchers, clinicians, and policymakers.